Products and methods for brachytherapy

ABSTRACT

A radioactive member for use in brachytherapy comprising a hollow elongate bioabsorbable suture member with radioactive seeds and spacer members without different coloration and diameter from the radioactive seeds alternately disposed therein, and methods for the manufacture and the use thereof. The radioactive members may be used in the treatment of, for example, prostate cancer.

FIELD OF INVENTION

The present invention relates generally to radiotherapy. Morespecifically, it relates to radioactive sources for use in brachytherapyand to methods for the preparation of such sources.

BACKGROUND OF THE INVENTION

Brachytherapy is a general term covering medical treatment whichinvolves the placement of a radioactive source near a diseased tissueand may involve the temporary or permanent implantation or insertion ofa radioactive source into the body of a patient. The radioactive sourceis thereby located in proximity to the area of the body which is beingtreated. This has the advantage that a high dose of radiation may bedelivered to the treatment site with relatively low dosages of radiationto surrounding or intervening healthy tissue.

Brachytherapy has been proposed for use in the treatment of a variety ofconditions, including arthritis and cancer, for example breast, brain,liver and ovarian cancer and especially prostate cancer in men (see forexample J. C. Blasko et al., The Urological Clinics of North America,23, 633-650 (1996), and H. Ragde et al., Cancer, 80, 442-453 (1997)).Prostate cancer is the most common form of malignancy in men in the USA,with more than 44,000 deaths in 1995 alone. Treatment may involve thetemporary implantation of a radioactive source for a calculated period,followed by its removal. Alternatively, the radioactive source may bepermanently implanted in the patient and left to decay to an inert stateover a predictable time. The use of temporary or permanent implantationdepends on the isotope selected and the duration and intensity oftreatment required.

Permanent implants for prostate treatment comprise radioisotopes withrelatively short half lives and lower energies relative to temporarysources. Examples of permanently implantable sources include iodine-125or palladium-103 as the radioisotope. The radioisotope is generallyencapsulated in a casing such as titanium to form a “seed” which is thenimplanted. Temporary implants for the treatment of prostate cancer mayinvolve iridium-192 as the radioisotope.

Conventional radioactive sources for use in brachytherapy includeso-called seeds, which are sealed containers, for example of titanium,containing the radioisotope within a sealed chamber but permittingradiation to exit through the container/chamber walls (U.S. Pat. No.4,323,055 and U.S. Pat. No. 3,351,049). Such seeds are only suitable foruse with radioisotopes which emit radiation which can penetrate thechamber/container walls. Therefore, such seeds are generally used withradioisotopes which emit γ-radiation or low-energy X-rays, rather thanwith β-emitting radioisotopes.

Radioactive seeds are generally loaded into needles, with the needlesthen being inserted into the treatment site, such as prostate, usingultrasound imaging to guide the insertion process. The radioactive seedsare either positioned independently within the needles and hence arelocated independently within the treatment site after they have beenmoved out of the needle, or they are connected in a string arrangementby being loaded within a hollow, absorbable suture member.

U.S. Pat. No. 5,460,592 discloses a method and apparatus fortransporting a radioactive device. The device comprises a flexible,elongated woven or braided bio-absorbable carrier material having spacedradioactive seeds disposed therein. On heating, the carrier materialholding the seeds becomes semi-rigid. A length of the semi-rigid carriermaterial with radioactive seeds disposed therein may then be loaded intoa conventional, hollow metal dispensing needle or applicator cartridgewhich is used to implant the radioactive seeds into or contiguous to thetreatment site, for example a tumour.

A commercial product consisting of iodine-125 seeds regularly spaced atbetween 0.6 and 1.2 cm centre to centre inside a braided, semi-rigidbioabsorbable suture material is available from Medi-Physics Inc. underthe trade name 1-125 RAPID Strand™. This product may be used to treatconditions such as head and neck cancers, including those of the mouth,lips and tongue, brain tumours, lung tumours, cervical tumours, vaginaltumours and prostate cancer.

One advantage of this type of suture/radioactive seed combination isthat the radioactive seeds are implanted or inserted into a patient witha pre-determined spacing, depending on their spacing in the suturematerial. The bioabsorbable material is then slowly absorbed into thepatient's body to leave the spaced seeds in position. This predeterminedspacing and the semi-rigid nature of the suture aids a physician incalculating both the total radiation dose and the dose profile whichwill be delivered by the seeds inside a patient's body, and also aids inaccurate placement of the seeds. In addition, more than one seed isimplanted at once, so lessening the time taken for implantation overthat required for the placement of individual loose seeds. The risk ofseed migration away from the site of implantation is also reduced (Tapenet al., Int. J. Radiation Oncology Biol. Phys., vol. 42(5), pages1063-1067, 1998).

Another advantage of the hollow suture combination over independentseeds approach is that the independent seeds, even once in the treatmentsite, for example prostate, could migrate out of the prostate to variousother locations in the body, including lungs. Migrated seeds can reduceimplant quality and also potentially harm the patient.

However, this hollow suture combination has limitations on long axisstrength due to the void areas, introduced into the arrangement duringmanufacturing, used for the spacing between the radioactive seeds. Thisvoid area long axis strength is limited to the strength of the suturematerial. Although the void area strength is increased during the heatstiffening manufacturing process, the resulting strength is still notideal. Due to this limitation, the suture combination can sometimes jamwithin the insertion needle, resulting in a collapsing of the suturecombination in the void area between the radioactive seeds. Thiscondition requires removal of the needle from the prostate and thesubsequent reloading of the needle with independent radioactive seeds.This alteration of technique is time-consuming and expensive in nature.

One approach to remedy the situation is disclosed in U.S. Pat. No.6,264,600. It discloses a method and apparatus including a hollow suturewith alternating plurality of radioactive seeds and intermediatespacers. While this suture/seed combination offers stronger long axisstrength, there are several areas that can be improved upon.

First, there is still need for even more long axis strength to reducethe possibilities of suture jamming within the insertion needle.

Further, both hollow suture/seed combination and current hollowsuture/seed/spacer combination is singular in color, with onlydimensional differences in seeds and void areas of the assembly. Thislimitation can cause uncertainty in preparing the combination inimplant. The current fixture only allows cutting in the void areas ofthe suture combination, away from the critical radioactive seedcomponent. However, this becomes impossible once the suture combinationis removed from the fixture.

Finally, current suture/seed/spacer combination has similar diametersfor both seed and spacer. This lack of dimensional difference makescutting more difficult.

There is therefore a need for an improved radioactive source which doesnot suffer from all the disadvantages of the known sources, and whichcan preferably be produced using an automated manufacturing process.

SUMMARY OF THE INVENTION

In one aspect of the invention there is therefore provided a radioactivemember for use in brachytherapy comprising a hollow elongatebioabsorbable suture member with a plurality of radioactive seeds andspacer members disposed alternately therein, wherein the spacer membersare dyed with a different color from that of the undyed radioactiveseeds and of different diameter from that of the radioactive seeds. Theradioactive seeds and the spacer members are preferably retained thereinby deformation of the suture member on heating, followed by subsequentcooling.

In a further aspect of the invention, there is provided a radioactivemember for use in brachytherapy comprising a hollow elongatebioabsorbable suture member with one or more slots therein in which oneor more radioactive seeds and spacer members are disposed alternately ina spaced relationship, wherein the spacer members are dyed with adifferent color from that of the undyed radioactive seeds and ofdifferent diameter from that of the radioactive seeds. Preferably, thesuture member is essentially stiff. The slots may comprise a continuousgroove or a series of discrete openings longitudinally spaced along thesuture material. Preferably, the radioactive seeds and spacers aresecurely retained in the suture member by heat sealing.

As a further feature of the invention there is provided a method for theproduction of a radioactive member for use in brachytherapy comprisingan elongate, bioabsorbable suture member with radioactive seeds andspacer members disposed alternately therein, said method comprising thesteps of:

-   -   a) providing a hollow bioabsorbable suture member,    -   b) providing a plurality of radioactive seeds,    -   c) providing a plurality of bioabsorbable spacer members,        wherein the spacer members are dyed with a different color from        that of the undyed radioactive seeds and of different diameter        from that of radioactive seeds,    -   d) heating the radioactive seeds to a temperature above the        melting or softening temperature of the suture material,    -   e) placing the heated seeds and spacer members alternately onto        the suture member in a predetermined pattern whereby the suture        member melts or deforms around each source and spacer member,        and    -   f) cooling the suture member such that it solidifies or hardens        about each source and spacer member so as to securely retain        each source in place.

In an alternative embodiment of the method, in steps d) and e), thesuture member may itself be at an elevated temperature (at which it doesnot lose its integrity), for example following extrusion, and theradioactive seeds and spacer members then placed onto the suture membersuch that they are held in place as it cools. In such a method, theradioactive seeds may be cold or may themselves also be heated.

In step e), an external force may also optionally be applied to deformor to further deform the suture member around the radioactive seeds andthe spacer members. For example, heated plates may be applied to theexterior of the suture member to further melt the suture member aroundthe radioactive seeds and the spacer members to hold them in place.

In yet another embodiment of the method, it further comprises a step ofsterilizing the radioactive member.

In another embodiment of the invention, there is provided a method ofusing the radioactive member for brachytherapy, said method comprising:

-   -   a) cutting the radioactive member at one of the spacer members        to a prescribed length according to the prescribed implant plan;    -   b) inserting the cut radioactive member into a hub end of a        hollow insertion needle suitable for insertion into a prescribe        treatment area, so that the entire radioactive member is inside        the needle;    -   c) pushing the radioactive member through the hollow insertion        needle with a needle stylet, until the leading tip of the        radioactive member reaches a needle plugging media;    -   d) inserting the loaded insertion needle into the prescribed        treatment area of a patient;    -   e) removing the insertion needle from around the radioactive        member, leaving the radioactive member in the prescribed        treatment area of the patient.

In yet another embodiment of the invention, there is provided anothermethod of using the radioactive member for brachytherapy, said methodcomprising:

-   -   a) inserting an insertion needle into a prescribed treatment        area of a patient;    -   b) cutting the radioactive member at one of the spacer members        to a prescribed length according to the prescribed implant plan;    -   c) loading the radioactive member into an after-loading device;    -   d) transferring the radioactive member in the after-loading        device to the insertion needle where it mates into the insertion        needle hub;    -   e) applying a stylet to advance the radioactive member through        the after-loading device into the insertion needle, and finally        into the patient;    -   f) removing the insertion needle and the after-loading device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of the improved suture combination ofthe present invention.

FIG. 2 shows a partial, exploded view of the elongated seed suturemember and radioactive seeds located in first and second recesses of ajig member with knife edge slots traversing the first and secondrecesses.

FIG. 3 shows a segment of the prepared radioactive member being loadedinto a brachytherapy needle before implantation into a patient.

FIG. 4 shows a segment of the prepared device being loaded into aafter-loading device and then into a brachytherapy needle at the time ofimplantation into a patient.

FIG. 5 depicts an alternate embodiment of the improved suturecombination of the present invention.

FIGS. 6A-E depict cross-sectional views of various improved suturecombinations of the present invention.

FIG. 7 depicts alternative embodiments of the features for the outersurface of a member of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring to the drawings, FIG. 1 shows a cross-section of oneembodiment of the invention: a radioactive member for use inbrachytherapy comprising a hollow elongate bioabsorbable suture member 3with radioactive seeds 2 and spacer members 1 alternately dispersedtherein.

Radioactive seeds 2 are typically 0.5 mm to 1 mm in diameter and 4 mm to5 mm in length. However, dimensions of radioactive seeds can vary. Thespacer members can be of fixed or variable length between eachradioactive seed. The spacer members are on both the leading andtrailing edges of the radioactive member.

Coloration in spacer members may be used to create a color scheme toeasily identify components inside the suture member. Spacer members 1may be dyed, for example, violet, to distinguish from undyed suturemember 3. Diameter size of the spacer members 1, in comparison todiameter size of the radioactive seeds 2, may be different, such asreduced, to easily identify components inside the suture member 3. Heatstiffening of the radioactive member during the manufacturing processincreases the long axis rigidity, adheres the suture member 3 to theinternal radioactive seeds 2 and spacer members 1, and allows colorationto transfer from the spacer members 1 to suture member 3 for easyidentification of components.

The suture member and spacer member can be made of the same material.They may be any non-toxic, bio-compatible, bioabsorbable material or amixture of such materials. As used herein, a bioabsorbable material isany material of which a substantial portion will be metabolized within apatient's body and ultimately eliminated therefrom. Suitablebioabsorbable materials include poly(glycolic acid) (PGA) andpoly(lactic acid) (PLA), polyester amides of glycolic or lactic acidssuch as polymers and copolymers of glycolate and lactate, polydioxanoneand the like. Such materials are more fully described in U.S. Pat. No.5,460,592 which is hereby incorporated by reference. Suitablecommercially available polymers include polyglycaprone 25 (MONCRYL™),polyglactin 910 (VICRYL™) and polydioanone (PDS II), all available fromEthicon, Inc. of New Jersey, U.S.A.

Other suitable bioabsorbable polymers and polymer compositions that maybe used in this invention are described in the following patents whichare hereby incorporated by reference: U.S. Pat. No. 4,052,988 whichdiscloses compositions comprising extruded and oriented filaments ofpolymers of p-dioxanone and 1,4-dioxepan-2-one; U.S. Pat. No. 3,839,297which discloses compositions comprising poly[L(-)lactide-co-glycolide]suitable for use as absorbable sutures; U.S. Pat. No. 3,297,033 whichdiscloses the use of compositions comprising polyglycolide homopolymersas absorbable sutures; U.S. Pat. No. 2,668,162 which disclosescompositions comprising high molecular weight polymers of glycolide withlactide; U.S. Pat. No. 2,703,316 which discloses compositions comprisingpolymers of lactide and copolymers of lactide with glydolide; U.S. Pat.No. 2,758,987 which discloses compositions comprising optically activehomopolymers of L(-) lactide i.e. poly L-Lactide; U.S. Pat. No.3,636,956 which discloses compositions of copolymers of L(-) lactide andglycolide having utility as absorbable sutures; U.S. Pat. No. 4,141,087which discloses synthetic absorbable crystalline isomorphiccopolyoxylate polymers derived from mixtures of cyclic and linear diols;U.S. Pat. No. 4,441,496 which discloses copolymers of p-dioxanone and2,5-morpholinediones; U.S. Pat. No. 4,452,973 which disclosespoly(glycolic acid)/poly(oxyalkylene) ABA triblock copolymers; U.S. Pat.No. 4,510,295 which discloses polyesters of substituted benzoic acid,dihydric alcohols, and glycolide and/or lactide; U.S. Pat. No. 4,612,923which discloses surgical devices fabricated from synthetic absorbablepolymer containing absorbable glass filler; U.S. Pat. No. 4,646,741which discloses a surgical fastener comprising a blend of copolymers oflactide, glycolide, and poly(p-dioxanone); U.S. Pat. No. 4,741,337 whichdiscloses a surgical fastener made from a glycolide-rich blend ofpolymers; U.S. Pat. No. 4,916,209 which discloses bioabsorbablesemi-crystalline depsipeptide polymers; U.S. Pat. No. 5,264,540 whichdiscloses bioabsorbable aromatic polyanhydride polymers; and U.S. Pat.No. 4,689,424 which discloses radiation sterilizable absorbable polymersof dihydric alcohols.

Bioabsorbable polymers and polymer compositions are especially usefulwhen they comprise bioabsorbable fillers such as those described in U.S.Pat. No. 4,473,670 (which is incorporated by reference) which disclosesa composition of a bioabsorbable polymer and a filler comprising apoly(succinimide); and U.S. Pat. No. 5,521,280 (which is incorporated byreference) which discloses bioabsorbable polymers and a filler of finelydivided sodium chloride or potassium chloride. Such fillers can provideincreased stiffness to bioabsorbable polymers and polymer compositions.

Poly(glycolic acid) has a melting point of either 230° C. to 260° C. anda glass transition point of 45° C. to 50° C. (Materials Safety DataSheet, Medisorb Lactide/Glycolide Polymers). If this is used as thesuture material, then in steps d) and e) of the methods of the inventionthe sources, the spacer member and/or the suture member should be heatedto at least this glass transition point temperature.

The bioabsorbable material should preferably maintain its integrity onceimplanted for from about 1 to 14 days. This helps to ensure that thespacing of the sources is maintained for at least a short periodpost-implantation. Use of the radioactive members of the invention alsohelps ensure proper dosimetry and minimizes source movement or shedding.Preferably the suture member should be fully absorbed by living tissueover a total of about 70 to 120 days.

By “essentially stiff” is meant that the suture member and the spacermember should have some structural integrity and be stiff enough for itsproposed uses. The suture member and spacer member should be stiffenough to maintain the spacing between the radioactive seeds duringstorage, shipment and implantation of the radioactive member. If thesuture member and spacer member have melted and deformed when heated bythe seeds so as to trap the radioactive seeds in place, it should thenre-stiffen when cooled.

In addition, the suture member should be formable into an elongateshape. Preferably, once in an elongate shape, the suture member and thespacer member should be easy to cut using for example a scalpel or thelike. Preferably, diameter of the spacer members is different from thatof the radioactive seeds, so that the spacer member can be easilyidentified inside the suture material. For example, diameter of thespacer members can be 0.1 mm to 0.5 mm smaller than that of theradioactive seeds. Coloration in spacer members, such as violet, may beused to create a color scheme to easily identify components inside thesuture member. Dyed spacer members can be easily distinguished fromundyed suture member. The suture member should also preferably have anappreciable shelf life without the need for any special storage orhandling conditions. The suture member should also be sterilizable byany conventional sterilisation method, such as for example using steam,dry heat, ethylene oxide, electron-beam or gamma-radiation, as well aspulse-light sterilization method. Preferred sterilization method isethylene oxide.

The suture member should have an internal diameter sufficient toaccommodate the radioactive seeds and spacer members. As depicted inFIGS. 6A-6E, where ‘S’ depicts a seed or spacer and ‘C’ depicts thesuture or carrier material, the suture member of the present inventionmay be of any suitable cross-section, for example substantially circular(FIG. 6B), substantially circular with at least one flattened surface(FIG. 6A), or substantially polygonal, for example, square (FIG. 6D) ortriangular (FIG. 6E). A preferred suture according to the invention hasa substantially square cross-section, both for ease of manufacture andto limit the surface area of the suture which will be in contact withthe inside of the dispensing needle, so making jamming of the suturewithin the needle due to friction between the needle and the surface ofthe suture less likely. Reduced friction could also be achieved with anycross-section having at least one flat surface e.g. a substantiallycircular cross-section flattened at a region on the circumference togive a flat surface. Suitable sutures are substantially polygonal inshape, for example, hexagonal, octagonal, or 12 or 16-sided etc. Thus,another preferred suture in accordance with the invention issubstantially octagonal (FIG. 6C). A substantially triangularcross-section is also preferred, as it offers one less edge than asubstantially square cross-section to contact the inner walls of adelivery needle device.

The length of the suture member can vary. Preferably, a radioactivemember contains 2 to 15 radioactive seeds.

The surface contact between the inner surface of a needle or otherdelivery device and a suture of any cross sectional shape can be furtherminimized by the provision of suitable surface structures on the suturesurface which contacts the delivery device. For example, as depicted inFIG. 7, in the case of a curved suture surface, surface contact can bereduced by incorporating ridges 20, spheres 30, or other protrusions 40in the area of the suture surface that contacts the needle or deliverydevice surface. Preferably, these surface structures comprisebiocompatible or biodegradable suture material. A suitable method forforming such surface structures comprises application of a heated mouldor press plate, the surface of which is configured as a negative of thestructures being applied to the suture. Upon application of the heatedmould to the surface of the suture, the suture will flow into thecavities in the negative mould. Release of the suture from the mould andcooling of the suture will impart to the suture surface a positiveimage, reciprocal to the negative image of the mould. Beads or bumpsproduced on the surface of the suture provide reduced contact area andless friction between the suture and a needle used as a delivery device.

Preferably, the suture will be visible using ultrasound imagingtechniques. For example, as depicted in FIG. 5, it may comprise soundreflecting particles or bubbles of gas, generally represented as “10”,which serve to enhance its ultrasound visibility. If the suture is apolymer, bubbles of gas may be trapped in the polymer during theextrusion process to form a suture, for example by blowing bubbles intothe polymer as it is extruded. Alternatively, the polymer may beagitated (e.g. by sonication) prior to extrusion under a suitable gasatmosphere such that bubbles of gas are incorporated therein. Suitablegases include air, nitrogen, carbon dioxide, Freons and fluorocarbonssuch as perfluorobutane.

Alternatively, the suture member may be subjected to a gas underpressure, for example greater than atmospheric pressure, immediatelyprior to extrusion such that the gas becomes dissolved into thematerial. Upon extrusion combined with a reduction in the pressure ofgas due to warming (such as on extrusion into an ambient pressure andtemperature environment), the gas will expand to form bubbles in thesuture member. Preferably, the bubbles are at or near the surface of thesuture member.

The suture can be uniformly visible or non-uniformly visible byultrasound. For example, some regions of the suture may be more visibleby ultrasound than other regions. This can arise due to the presence ofregions where clusters of sound reflecting gas bubbles or particlesreside in a suture.

The suture may additionally or alternatively comprise particles whichserve to enhance its visibility to ultrasound. Suitable particlesinclude particles of metal (for example titanium or aluminum), glass,silica, iron oxide, sand, clay, plastics such as TEFLON™, porousuniformly-sized non-aggregated particles as described in U.S. Pat. No.5,741,522 and U.S. Pat. No. 5,776,496 which are hereby incorporated byreference, hollow microcapsules or solid microspheres such as thosedisclosed in U.S. Pat. No. 5,648,095 which is hereby incorporated byreference, and microspheres of a fused sugar, a fused amino acid or ofPEG (polyethylene glycol).

One advantage of using imaging-visible, for example ultrasound-visible,radioactive members of the invention in brachytherapy is that the signaland image may be read, measured and analysed by suitable computersoftware sufficiently quickly to allow a physician to plan real-timedosimetry. This is advantageous from a clinical view point for bothpatient and medical personnel. However, the members of the invention maybe used in processes involving any type of dosimetry mapping that usesinformation obtained due to the imaging visibility of the radioactiveseeds.

In addition, a physician may use the same imaging technique, for exampleultrasound, already in place during surgery to confirm both organ (e.g.prostate) position and size, and radioactive seeds placement. This couldenable a physician to calculate if additional radioactive seeds need tobe inserted, for example in situations where the dose pattern needs tobe recalculated based on the actual, implanted position of the sources.

The overall dimensions of the suture member should be such that it willfit inside a dispensing needle or applicator cartridge. For example, ifthe internal diameter of a thin walled 18 gauge needle is 0.102 cm(0.040 inches), then the effective maximum diameter of the suture ispreferably less than 0.102 cm (0.040 inches), so that it can bedispensed from such needles.

The suture can be uniformly or non-uniformly distributedcross-sectionally around the sources. For example where the sources aresubstantially cylindrical radioactive seeds, the shape of thecross-section of the internal surface of the suture could, preferably besubstantially round. In an alternative embodiment, the surface could besubstantially square.

Any conventional radioactive seed may be used as the radioactive source.These include for example the radioactive seeds disclosed in U.S. Pat.No. 5,404,309, U.S. Pat. No. 4,784,116, U.S. Pat. No. 4,702,228, U.S.Pat. No. 4,323,055 and U.S. Pat. No. 3,351,049 which are herebyincorporated by reference. By “seed” is meant any sealed container, forexample a metal container, containing or encapsulating a radioisotope.Suitable biocompatible container materials include metals or metalalloys such as titanium, gold, platinum and stainless steel; plasticssuch as polyesters and vinyl polymers, and polymers of polyurethane,polyethylene and poly(vinyl acetate); composites such as graphite; glasssuch as matrices comprising silicon oxide, and any other biocompatiblematerial. Titanium and stainless steel are preferred materials for thecontainers.

The radioactive seeds may also comprise a suitable radioisotopeencapsulated within a polymer or ceramic matrix.

Typical radioactive seeds are substantially cylindrical in shape.Dimensions of a typical seed can be approximately 4.5 mm long with adiameter of approximately 0.8 mm.

Any radioisotope suitable for use in brachytherapy may be used in theradioactive seeds. Non-limiting examples include palladium-103,iodine-125, strontium-89, sulphur-35, cesium-131, gold-198, thulium-170,chromium-56, arsenic-73, yttrium-90, phosphorus-32 and mixtures thereof.Especially preferred are palladium-103 and iodine-125. More than onetype of radioisotope may be present in the radioactive seeds for use inthe invention.

The radioactive seeds and spacer members are preferably loaded linearlyalong the longest axis of the elongate suture member. The orientation ofthe radioactive seeds relative to the suture will depend on the overallsize and shape of the suture and the radioactive seeds. If theradioactive seeds are substantially cylindrical in shape, for example ifthey are conventional seeds, then they are preferably orientated withtheir longitudinal axes parallel to the longitudinal axis of theelongate suture itself. Preferably, the radioactive seeds are regularlyspaced, for example at intervals of between 0.6 and 1.2 cm, preferablyat about 1 cm intervals. A spacing of about 1 cm is preferred if thesources are to be implanted for treatment of prostate cancer. Spacermembers of suitable lengths are placed between seeds. The number ofradioactive seeds used for any particular application will depend on thelength of suture member used. Preferably, the radioactive member isprovided as a long strip which can then be cut or snapped to the desiredlength for a particular application by the medical staff.

Preferably, all the radioactive seeds in one suture will contain thesame radioisotope and/or be of the same radioactive strength. If morethan one type or strength of source is included in one suture, then thedifferent radioactive seeds should be arranged in a regular pattern toallow predictable dosing.

Preferably, the radioactive member may then be inserted into a jig toform a jig assembly. Such jigs disclosed in U.S. Pat. No. 5,460,592hereby incorporated by reference. FIG. 2 shows the radioactive seed 2 ofthe radioactive member and its placement inside a jig 4. The jig 4allows for a fixed position of the radioactive seeds 2 and spacermembers 1, for subsequent manufacturing steps (stiffening),transportation and also for preparation of segments for implant(cutting).

The jig assembly is then dry heated. The dry heat causes the suturemember to become rigid. This stiffening process can take place in aprocess at 160° C. to 190° C. for 60 to 90 minutes.

As a still further feature of the invention there is provided a furthermethod for the production of a radioactive member for use inbrachytherapy comprising a hollow elongate bioabsorbable suture memberwith radioactive seeds and spacer members disposed alternately therein,said method comprising the steps of:

-   -   a) providing an elongate preferably single stranded        bioabsorbable suture member having a longitudinal groove or slot        therein,    -   b) providing a plurality of radioactive seeds,    -   c) providing a plurality of bioabsorbable spacer members,        wherein the spacer members are of a different color from that of        the radioactive seeds and of different diameter from that of the        radioactive seeds;    -   d) placing the radioactive seeds and the spacer members        sequentially or concurrently into the groove in the suture        member such that the radioactive seeds and the spacer members        are securely retained within the groove.

FIG. 5 depicts a member 3 in which the suture includes a slot 9. Seeds 2and spacers 1 are seen through slot 9. Preferably, the groove or slotwill be diametrically opposed to a flat surface of the cross section ofthe suture. For example, where the suture is substantially round withone flattened surface, the groove or slot will be positioned opposite tothis flat surface. This would allow for ease of orientation duringmanufacture for example, the suture member could be orientated with theslit uppermost using the flat surface for reference so that the sourcescould be readily pushed into the groove.

Preferably, the groove or slot will be shaped such that once a source isplaced therein it is securely retained. For example, the opening to thegroove may be slightly narrower than the groove itself and the width ofthe source such that the source must be “clipped” into place by pushingit through the opening, and is then retained within the groove. Forexample, a rail or elongate lip may be formed along the long axis of thesuture inside the groove and adjacent to the opening of the groove, suchthat the radioactive seeds and the spacer members, once pushed past therail or lip, are held in place inside the groove by the rail or lip.Alternatively, a series of suitably spaced protrusions, for exampleknobs or tabs, may be provided just inside the opening of the groove tohold the sources in place within the groove. Preferably, the rails, lipsor protrusions will be formed on both sides of the opening to thegroove.

Alternatively or additionally, the radioactive seeds and spacer membersmay be held in place by a suitable biocompatible adhesive. For example,a bead of a suitable adhesive or resin could be placed in the groovewith a source and then the adhesive or resin allowed to dry or a curingmethod used to dry it. Examples of suitable biocompatible adhesives areknown in the art and include epoxy adhesives such as Tra-Bond 2105, atwo part epoxy adhesive from Tra-Bond US (see Chem. Eng. News, 8 Dec.1997, 75 (49) p 40, hereby incorporated by reference); certain tyrosine-and lysine-containing heptapeptides and polypeptides as disclosed inJapanese Patent 05017499, hereby incorporated by reference; certainadhesives derived from polyphenolic proteins as disclosed in U.S. Pat.No. 5,015,677, hereby incorporated by reference; certain dental cementadhesives such as an adhesive composition comprising poly(methylmethacrylate) (PMMA) and 5% of 5-methacryloxyethyl trimellitic anhydridewith partially oxidized tibutylborane as disclosed in Proc. IUPAC,I.U.P.A.C., Macromol. Symp., 28^(th) (1982), 395, hereby incorporated byreference; and poly(propyl methacrylate), poly(methyl methacrylate),poly(butyl methacrylate-co-ethyl methacrylate), and silicone gels (seeProc. SPIE-Int. Soc. Opt. Eng, (1998), 3258, 164-168, herebyincorporated by reference).

Alternatively or additionally, the edges of the groove can be deformedor pinched together by application of an external force, for example byapplying a compression step in which the upper portion of the grooveedges above the widest part of the source are contacted with one or morewarmed or heated plates, baffles, flanges or diverting members whichmay, for example, comprise two plates oriented parallel to the axis ofthe suture and substantially perpendicular to a projected radius of theradioactive seeds and to each other such that interaction with thegroove edges produces a narrowing of the opening in the groove. This canbe done after the source is placed in the groove. Alternatively, arotating heated roller or wheel, configured to apply compression to thegrooves in the above manner may be used. The edge of the roller or wheelmay be concave to achieve this compression. The compression may becontinuous.

Alternatively, heated plates can be used to bend the edges of the grooveafter a source is placed into the groove. In a grooved opening of asuture material, the edges of the groove can be substantiallyperpendicular to the base of the groove. The edges of the groove canextend beyond the midpoint of the source, for example beyond the widestpart of the source (such as the diameter of a substantially circularsource) when viewed from the end of the source when the source is placedinto the groove. With the source in the groove, heated plates, baffles,flanges or diverting members can be applied from above or beside thevertical groove edges to contact the vertical edges above the widestpart of the source. The heated plates then soften the vertical grooveedges and the mechanical force causes the edges to bend over the source,thereby pinching the source in place. Removal of the heated platesallows the bent edges to cool and thenceforth hold the source tightly inplace in the grooved suture.

In another embodiment, a heated rotating wheel or roller configured toapply compression to the upper edges of the groove may be used to narrowthe opening of a groove after a radioactive seed has been placedtherein. A suture with one or more radioactive seeds and spacer membersin place within the groove may be fed under a heated rotating wheel orroller, such that part of the wheel or roller contacts the area of thesuture adjacent to the opening of the groove, causing it to soften ormelt and so deform around the source to hold it in place. Preferably,the part of the roller or wheel contacting the suture will have aconcave surface such that the edges of the groove may be deformed orpinched together to form a completely or partially closed tubecontaining the sources. Contact between a given portion of the sutureand the wheel or roller can be temporary as the wheel or roller rotates.Optionally, the suture may be constrained to bend and follow thecircumference of the wheel or roller and be held under tension tostretch, compress or further form it.

The suture may be fed under the wheel or roller in a continuous process.Optionally, the part of the wheel or roller contacting the suture maycomprise a positive or negative mould such the contact with the suturetransfers a reciprocal pattern, for example comprising ridges or bumps,to the suture.

Alternatively or additionally, after loading with radioactive seeds andspacer members, the suture can be encased within a suitable coating, forexample of Vicryl™ braid, to hold the radioactive seeds and spacermembers in place inside the groove or the discrete openings.

At the end of the manufacturing process, the radioactive member may becut to suitable lengths and each length loaded separately into a jig,such as the jig disclosed in U.S. Pat. No. 5,460,592. The jig assemblycan then be stiffened by a dry heat process as described in a previousembodiment.

Optionally, the radioactive member of the invention will be shielded forshipping from the manufacturing site to the site of use. Preferably,after packaging, the product will be sterilized, for example by anyconventional sterilisation procedure such as autoclave, gammairradiation, ethylene oxide sterilisation or pulse light sterilization.The product can then be shipped from the manufacturer to the site of useas a sterile unit which, once removed from the packaging and shielding,is ready for the member to be used.

The radioactive members of the invention may be used in the treatment ofa range of conditions including head and neck cancers (including thoseof the mouth, lips and tongue) brain tumours, lung tumours, cervicaltumours, vaginal tumours and prostate cancer. They may be used as aprimary treatment (for example in the treatment of prostate cancer orunresectable tumours) or for treatment of residual disease afterexcision of the primary tumour. They may be used concurrently with, orat the completion of, other treatment modalities, for example externalbeam radiation therapy, chemotherapy or hormonal therapy.

The radioactive members of the invention may be used alone or incombination with individual radioactive sources, for example seeds.

As a further aspect of the invention, there is also provided a method oftreatment of a condition which is responsive to radiation therapy, forexample cancer or arthritis, especially prostate cancer, which comprisesthe placement of a radioactive member comprising an essentially stiffelongate, single stranded bioabsorbable suture member with spacedradioactive sources disposed therein at or adjacent the site to betreated within a patient for a sufficient period of time to deliver atherapeutically effective dose.

In a preferred embodiment, the radioactive member may be visualisedusing a suitable imaging technique, preferably ultrasound imaging, inconnection with real-time dosimetry equipment.

The radioactive members of the invention may be administered to apatient by placing a suitable length of suture into the tip of a hollowneedle and then placing a stylet into the needle, as shown in FIG. 3.The needle 5 may be inserted into a patient and then pulled back overthe stylet leaving the suture in place. For methods of administrationsee, for example, A. van't Riet et al., Int. J. Radiation Oncology Biol.Phys., Vol. 24, pages 555-558, 1992, hereby incorporated by reference.

For example, radioactive member 7 can be prepared to the required lengthaccording to the prescribed implant plan. This preparation includesremoving the radioactive member from the packaging and sterility barrierand cutting through a spacer member to the prescribed length. Theradioactive member, cut to the prescribed length, is then inserted intoan insertion needle, through a hub end 6 thereof, to the point where theentire assembly is completely inside the needle 5. The radioactivemember is then pushed through the hollow insertion needle, with a needlestylet, until the leading tip of the radioactive member reaches a needleplugging media, such as bone wax. The loaded insertion needle is theninserted into a prescribed treatment area of a patient, for example,prostate. The insertion needle is subsequently removed, leaving theradioactive member in the prescribe treatment area. The radioactivemember is provided sterile for immediate preparation and use.

An alternate method of insertion needle loading would include the use ofan after-loading device, as shown in FIG. 4. In this embodiment, theinsertion needle 5 can be inserted into the prescribed treatment area ofa patient, for example, prostate, in advance of loading the radioactivemember, following the pre-operative implant plan. The radioactive member7, prepared to the prescribed length, is then loaded into anafter-loading device 8, which temporarily houses the radioactive member.When required, the radioactive member is then transferred to theinsertion needle where it mates into the insertion needle hub. A styletis then used to advance the radioactive member through the after-loadingdevice, into the needle, and finally into the patient.

The invention described and claimed herein is not to be limited in scopeby the specific embodiments herein disclosed, since these embodimentsare intended as illustration of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

1. A radioactive member for use in brachytherapy comprising a hollowelongate bioabsorbable suture member with a plurality of radioactiveseeds and spacer members disposed alternately therein, wherein thespacer members are dyed with a different color from that of the undyedradioactive seeds and of different diameter from that of the radioactiveseeds and the dye of the spacer members transfers to the suture memberso as to identify the location of the spacer members within the suture.2. A radioactive member of claim 1, wherein the diameter of the spacermember is 0.1 mm to 0.5 mm smaller than that of the radioactive seeds.3. A radioactive member of claim 1, wherein the spacer member is dyedwith violet.
 4. A radioactive member as claimed in claim 1 wherein thesuture member comprises poly(glycolic acid), poly(lactic acid), apolyester amide of glycolic or lactic acid, or a polydioxanone.
 5. Aradioactive member as claimed in claim 1 wherein the suture has asubstantially circular cross section.
 6. A radioactive member as claimedin claim 1 characterised in that the cross section of the suture has atleast one flat surface.
 7. A radioactive member as claimed in claim 1wherein the suture has a substantially polygonal cross-section and is,preferably, substantially octagonal, square or triangular.
 8. Aradioactive member as claimed in claim 1 wherein the suture comprisesultrasound reflecting particles or bubbles of gas.
 9. A radioactivemember of claim 1 loaded onto a wheel or a jig.
 10. A radioactive memberof claim 9 wherein the wheel or jig is shielded.
 11. A radioactivemember for use in brachytherapy comprising a hollow elongatebioabsorbable suture member with one or more slots therein in which oneor more radioactive seeds and spacer members are disposed alternately ina spaced relationship, wherein the spacer members are dyed with adifferent color from that of the undyed radioactive seeds and ofdifferent diameter from that of the radioactive seeds and wherein thedye of the spacer members transferred to the suture member so as toidentify the location of the spacer members within the suture.
 12. Amethod of treatment of a condition which is responsive to radiationtherapy which comprises the placement of a radioactive member of claim 1disposed therein at or adjacent the site to be treated within a patientfor a sufficient period of time to deliver a therapeutically effectivedose.
 13. A method of treatment of claim 12 wherein the condition totreated is prostate cancer.
 14. A method of claim 13 wherein theradioactive member is visualized using a suitable imaging technique inconnection with real-time dosimetry equipment.
 15. A method of claim 14wherein the imaging technique comprises ultrasound imaging.